Trisubstituted benzotriazole derivatives as dihydroorotate oxygenase inhibitors

ABSTRACT

The present invention provides methods for treating a cancer in a subject and for inhibiting tumor growth, metastasis or a dihydrorotate oxygenase enzyme activity of a tumor or cancer cell. At least one trisubstituted benzotriazole derivative with the formula (I) 
     
       
         
         
             
             
         
       
     
     is administered to the subject or is contacted with the cancer cell. Compounds of formula (I) have substituents R 1 , R 2  and R 3  which have the meanings given in the specification, and pharmaceutically acceptable salts thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/718,961, filed Sep. 28, 2017; which is a continuation of U.S. patentapplication Ser. No. 15/494,820, filed Apr. 24, 2017 and now U.S. Pat.No. 9,937,155; which is a continuation-in-part of U.S. patentapplication Ser. No. 14/784,708, filed Oct. 15, 2015 and now U.S. Pat.No. 9,630,932; which is the national stage of International ApplicationNo. PCT/IB2014/059204, filed Feb. 24, 2014; which claims the benefit ofpriority of Indian Provisional Patent Application No. 825/CHE/2013,filed on Feb. 25, 2013. All of the aforementioned applications arehereby incorporated by reference in their entireties.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to novel trisubstituted benzotriazolederivatives of formula (I) which are inhibitors of dihydroorotatedehydrogenase. In particular, the invention refers to novel compounds,which inhibits DHODH enzyme activity, to a process for their manufactureand pharmaceutical compositions containing them, and to their use forthe treatment and prevention in diseases or disorder, in particulartheir use in diseases or disorder where there is an advantage ininhibiting DHODH.

Description of the Related Art

DHODH is a protein that catalyzes one of the steps in denovo pyrimidinenucleotide biosynthetic pathway. (Greene et al. Biochem Pharmacol 1995,50:861-7; Davis J. P et al. FASEB J 1996, 10(6): Abst C23). It catalyzesthe only oxidation/reduction reaction in that pathway, which is the stepof converting DHO (dihydroorotate) to orotate with the aid of flavincofactor and an electron acceptor. Inhibitors of dihydroorotatedehydrogenase have been found to possess wider applications aschemotherapeutic agents. (Kensler et al. 1989 in: Design of EnzymeInhibitors as Drugs; Sandler, M., and Smith, H. J. Eds., pp 379-401Oxford Univ Press, Oxford England; Cody et al. Am. J. Clin. Oncol. 16,526-528 (1993)).

As an example for DHODH inhibitors, the quinoline derivative Brequinar(6-Fluoro-2-(2′-fluoro[1,1′-biphenyl]-4-yl)-3-methyl-4-quinolinecarboxylicacid) exhibits an anticancer activity towards L1210 murine leukemia(Andreson L W. Et al. Cancer Commun. 1989; 1(6), 381-7; Chen S F. et al.Cancer Res. 1986 October; 46(10): 5014-9). It has also been shown thatBrequinar potentiates 5-fluorouracil antitumor activity in a murinemodel colon 38 tumor by tissue-specific modulation of uridine nucleotidepools. (G Pizzorno et al. Cancer Res. 1992 Apr. 1; 52:1660-5).

DHODH inhibitors may also be useful in the treatment of viral mediateddiseases (see U.S. Pat. No. 6,841,561). Furthermore, inhibition of DHODHis known to be among promising target for treating transplant rejection,rheumatoid arthritis, psoriasis as well as autoimmune diseases (Kovarik,J. M. et al. Expert Opin. Emerg. Drugs 2003, 8, 47; Allison, A.C.Transplantation Proc. (1993) 25(3) Suppl. 2, 8-18); Makowka, L.,Immunolog Rev. (1993) 136, 51-70; Davis J. P et al. Biochemistry 1996,35: 1270-3).

Leflunomide, a well known DHODH inhibitor is a synthetic drug currentlymarketed, a low-molecular weight drug of the isoxazole class (seeEP0527736, JP1993506425, JP1999322700, JP1999343285, U.S. Pat. No.5,494,911, U.S. Pat. No. 5,532,259, WO19991017748) and used in thetreatment of Rheumatoid arthritis and is also under evaluation for usein the treatment of inflammatory bowel disease and chronic allograftrejection.

In vivo, Leflunomide is quickly transformed in its active metaboliteTeriflunomide that exerts its anti-inflammatory, antiproliferative andimmunosuppressive effects via mechanisms that are not completelyunderstood. Teriflunomide is not only a potential inhibitor of proteintyrosine kinase in vivo but a 100-1,000-fold greater inhibitor of DHODH(Davis J. P et al. FASEB J 1996, 10(6): Abst C23; Davis J. P et al.Biochemistry 1996, 35:1270-3).

With the rise in number of patients affected by autoimmune and relateddiseases, there is unmet need for new drugs that can treat such diseasesmore effectively. There is still a crucial need for immunosuppressiveagents, that are further useful in a wide variety of autoimmune andchronic inflammatory diseases, including systemic lupus erythematosus,chronic rheumatoid arthritis, multiple sclerosis, type I diabetesmellitus, inflammatory bowel diseases, biliary cirrhosis, uveitis andother disorders such as Crohn' s diseases, ulcerative colitis, bullouspemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener'sgranulomatosis, ichthyosis, Graves ophthalmopathy, atopic dermatitis andasthma. They may also be useful as part of chemotherapeutic regimens forthe treatment of cancers, lymphomas and leukemias, alone or incombination with antitumoral compounds well known by the one skilled inthe art.

SUMMARY OF THE INVENTION

The present invention is directed to a method for treating a cancer in asubject in need of such treatment. The method comprises the step ofadministering to the subject one or more times a therapeuticallyeffective amount of at least one compound according to formula (I):

or a pharmaceutically acceptable salt thereof. In the structure thedotted lines [....] in the ring may represent an optional bond which maybe present in any stable combination. R₁ may be hydrogen and alkyl. R₂may be -A-R₄. A may be arylene or tetrasubstituted arylene where thesubstituent is halogen. R₃ may be hydroxy and amino. R₄ may be anoptionally substituted aryl and an optionally substituted heteroaryl.The optional substituents may be one or more R₅. R₅ may be alkyl and—(CH₂)_(n)N(R_(a))R_(b). R_(a) and R_(b) may be independently hydrogen,alkyl and —C(O)alkyl or, alternatively, R_(a) and R_(b) can be takentogether with the nitrogen atom to which they are attached to form anoptionally substituted 4-6 membered heterocyclyl containing 0-2additional heteroatoms independently selected from O and N where theoptional substituent is alkyl and ‘n’ may be an integer 0 and 1.

The present invention also is directed to a method for inhibiting growthand/or metastasis of tumor cells in a subject. The method comprises thestep of administering to the subject one or more times a therapeuticallyeffective amount of at least one compound according to formula (I):

or a pharmaceutically acceptable salt thereof. In the structure thedotted lines [....] in the ring may represent an optional bond which maybe present in any stable combination. R₁ may be hydrogen and alkyl. R₂may be -A-R₄. A may be arylene or tetrasubstituted arylene where thesubstituent is halogen. R₃ may be hydroxy and amino. R₄ may be anoptionally substituted aryl and an optionally substituted heteroaryl.The optional substituents may be one or more R₅. R₅ may be alkyl and—(CH₂)_(n)N(R_(a))R_(b). R_(a) and R_(b) may be independently hydrogen,alkyl and —C(O)alkyl or, alternatively, R_(a) and R_(b) can be takentogether with the nitrogen atom to which they are attached to form anoptionally substituted 4-6 membered heterocyclyl containing 0-2additional heteroatoms independently selected from O and N where theoptional substituent is alkyl and ‘n’ ma be an integer 0 and 1.

The present invention is directed further to a method for inhibiting adihydroorotate oxygenase enzyme activity in a tumor cell. The methodcomprises the step of contacting the tumor cell one or more times with atherapeutically effective amount of at least one compound according toformula (I):

or a pharmaceutically acceptable salt thereof. In the structure thedotted lines [....] in the ring may represent an optional bond which maybe present in any stable combination. R₁ may be hydrogen and alkyl. R₂may be -A-R₄. A may be arylene or tetrasubstituted arylene where thesubstituent is halogen. R₃ may be hydroxy and amino. R₄ may be anoptionally substituted aryl and an optionally substituted heteroaryl.The optional substituents may be one or more R₅. R₅ may be alkyl and—(CH₂)_(n)N(R_(a))R_(b). R_(a) and R_(b) may be independently hydrogen,alkyl and —C(O)alkyl or, alternatively, R_(a) and R_(b) can be takentogether with the nitrogen atom to which they are attached to form anoptionally substituted 4-6 membered heterocyclyl containing 0-2additional heteroatoms independently selected from O and N where theoptional substituent is alkyl and ‘n’ ma be an integer 0 and 1.

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the present invention provides trisubstitutedbenzotriazole derivatives as dihydroorotate oxygenase inhibitors.

These derivatives are useful as medicament in treatment of autoimmuneand inflammatory disorders such as multiple sclerosis, rheumatoidarthritis and diseases like cancer.

In a particular embodiment, the present invention provides compounds offormula (I),

or a pharmaceutically acceptable salt or a pharmaceutically acceptableregioisomer thereof, wherein;

the dotted lines [....] in the ring represent an optional bond which maybe present in any stable combination;

R₁ is selected from hydrogen and alkyl;

R₂ is -A-R₄;

A is arylene or tetrasubstituted arylene; wherein the substituent ishalogen;

R₃ is selected from hydroxy and amino;

R₄ is selected from optionally substituted aryl and optionallysubstituted heteroaryl;

-   wherein the optional substituents are selected from one or more R₅;

R₅ is selected from alkyl and —(CH₂)_(n)N(R_(a))R_(b);

R_(a) and R_(b) are independently selected from hydrogen, alkyl and—C(O)alkyl;

alternatively R_(a) and R_(b) can be taken together with the nitrogenatom to which they are attached to form an optionally substituted 4-6membered heterocyclyl containing 0-2 additional heteroatomsindependently selected from O and N; wherein the optional substituent isalkyl; and

‘n’ is an integer selected from 0 and 1.

The embodiments below are illustrative of the present invention and arenot intended to limit the claims to the specific embodimentsexemplified.

According to one embodiment, specifically provided are compounds offormula (I), in which R₁ is alkyl; in particular alkyl is methyl.

According to another embodiment, specifically provided are compounds offormula (I), in which R₂ is -A-R₄, in which -A- is selected from aryleneand tetrasubstituted arylene.

According to preceding embodiment, specifically provided are compoundsof formula (I),

in which R₂ is selected from

According to one of the preceding embodiment, specifically provided arecompounds of formula (I), in which R₄ is selected from optionallysubstituted phenyl; in which optional substituents are selected frommethyl, acetylamino, isopropylaminomethyl, methylaminomethyl,dimethylaminomethyl,

According to one of the preceding embodiment, specifically provided arecompounds of formula (I), in which R₄ is selected from2,5-dimethyl-1H-pyrrole;

According to yet another embodiment, specifically provided are compoundsof formula (I), in which R₃ is —OH and —NH₂.

According to yet another particular embodiment, the compound of formula(I) is a compound of formula (Ia)

wherein, the dotted line [---], R₁, R₃ and R₄ are same as described informula (I).

According to yet another particular embodiment, the compound of formula(I) is a compound of formula (Ib)

wherein, the dotted line [---], R₁, R₃ and R₄ are same as described informula (I).

In another embodiment of the present invention, it provides the processfor preparation of trisubstituted benzotriazole derivatives of formula(I).

The procedure for the compounds of formula (I) is detailed herein belowin the specification stepwise including the general synthesis of variousintermediates involved in process of manufacture of the compoundsaccording to the present invention .

More particularly, the invention provides use of compounds of formula(I) or a pharmaceutically acceptable salt or a regioisomer thereof,including mixtures thereof in all ratios as a medicament, by inhibitingdihydroorotate oxygenase enzyme activity in treating disorder likemultiple sclerosis and other diseases such as inflammatory disorders,rheumatoid arthritis and cancer.

Trisubstituted benzotriazole derivatives of formula (I) of the presentinvention possess therapeutic role of inhibiting the dihydroorotatedehydrogenase (DHODH or DHOD) enzyme. The compounds of formula (I) maybe useful for treating and/or preventing, but not restricted to,autoimmune and chronic inflammatory diseases, including systemic lupuserythematosus, chronic rheumatoid arthritis, multiple sclerosis, type Idiabetes mellitus, inflammatory bowel diseases, biliary cirrhosis,uveitis and other disorders such as Crohn' s diseases, ulcerativecolitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmunemyositis, Wegener' s granulomatosis, ichthyosis, Graves ophthalmopathy,atopic dermatitis and asthma. The compounds of formula (I) and relatedformulae can be also useful as part of chemotherapeutic regimens for thetreatment of cancers, lymphomas and leukemias alone or in combinationwith classic antitumoral compounds well known by the one skilled in theart.

Without limiting the scope of present invention, the followingdefinitions are provided in order to aid those skilled in the art inunderstanding the detailed description of the present invention.

“Alkyl” refers to a hydrocarbon chain that may be a linear or branchedchain, containing the indicated number of carbon atoms, for example, aC₁-C₆ alkyl group may have from 1 to 6 (inclusive) carbon atoms in it.Examples of C₁-C₄ and C₁-C₆ alkyl groups include, but are not limitedto, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl,sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. An alkylgroup can be unsubstituted or substituted with one or more suitablegroups.

“Amino” refers to an —N— group, the nitrogen atom of said group beingattached to a hydrogen, alkyl, cycloalkyl, aryl, heterocyclyl or anysuitable groups. Representative examples of an amino group include, butare not limited to —NH₂, —NHCH₃ and —NH-cyclopropyl. An amino group canbe unsubstituted or substituted with one or more of the suitable groups.

“Aryl” refers to an optionally substituted monocylic, bicyclic orpolycyclic aromatic carbocyclic ring system of about 6 to 14 carbonatoms. Examples of a C₆-C₁₄ aryl group include, but are not limited tophenyl, naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl,indanyl, biphenylenyl, and acenaphthyl. Aryl group which can beunsubstituted or substituted with one or more suitable groups.

“Arylene” denotes a divalent monocyclic or bicyclic, saturated,unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atomswhich may be unsubstituted or substituted with one or more suitablegroups.

“Halogen” or “halo” includes fluorine, chlorine, bromine or iodine.

“Hydroxy” refers to —OH group.

The term “Heterocyclyl” includes the definitions of “heterocycloalkyl”and “heteroaryl”. The term “Heterocycloalkyl” refers to a non-aromatic,saturated or partially saturated, monocyclic or polycyclic ring systemof 3 to 10 member having at least one heteroatom or heterogroup selectedfrom O, N, S, S(O), S(O)₂, NH and C(O). Exemplary heterocycloalkylgroups include piperdinyl, piperazinyl, morpholinyl, thiomorpholinyl,1,3-dioxolanyl, 1,4-dioxanyl and the like. A heterocycloalkyl group canbe unsubstituted or substituted with one or more suitable groups.

“Heteroaryl” refers to an unsaturated, monocyclic, bicyclic, orpolycyclic aromatic ring system containing at least one heteroatomselected from oxygen, sulphur and nitrogen. Examples of C₅-C₁₀heteroaryl groups include furan, thiophene, indole, azaindole, oxazole,thiazole, thiadiazole, isoxazole, isothiazole, imidazole,N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole,N-methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole,1,2,4-triazole, 1-methyl-1,2,4-triazole, 1H-tetrazole,1-methyltetrazole, benzoxazole, benzothiazole, benzofuran,benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole,indazole, quinazoline, quinoline, and isoquinoline. Bicyclic heteroarylgroups include those where a phenyl, pyridine, pyrimidine or pyridazinering is fused to a 5 or 6-membered monocyclic heterocyclyl ring havingone or two nitrogen atoms in the ring, one nitrogen atom together witheither one oxygen or one sulfur atom in the ring, or one O or S ringatom. A heteroaryl group can be unsubstituted or substituted with one ormore suitable groups.

“Hetero atom” refers to a sulfur, nitrogen or oxygen atom.

“Optionally substituted or substituted” as used herein means that atleast one hydrogen atom of the optionally substituted group has beensubstituted with suitable substitutions as exemplified but not limitedto halogen, nitro, cyano, hydroxy, oxo (═O), thio (═S), —N(C₁-C₃alkyl)C(O)C₁-C₆alkyl), —NHC(O)(C₁-C₆alkyl), —NHC(O)(cyclo alkyl), —NHC(O)(aryl), —NHC(O)(heterocyclyl), —NHC(O)(heteroaryl), —NHC(O)H, —C(O)NH₂,—C(O)NH(C₁-C₆alkyl), —C(O)NH(cycloalkyl), —C(O)NH(heterocyclyl),—C(O)NH(hetero aryl), —C(O)N(C₁-C₆alkyl)(C₁-C₆alkyl),—S(O)NH(C₁-C₆alkyl), —S(O)₂NH(C₁ -C₆alkyl), —S(O)NH(cycloalkyl),—S(O)₂NH(cycloalkyl), carboxy, —C(O)O(C₁-C₆alkyl), —C(O)(C₁-C₆alkyl),=N—OH, substituted or unsubstituted alkyl, substituted or unsubstitutedhaloalkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted haloalkoxy, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted arylalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substitutedor unsubstituted cycloalkenyl, substituted or unsubstituted amino,substituted or unsubstituted heteroaryl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted heteroarylalkyl, substitutedor unsubstituted heterocyclic ring.

The particular compounds of the present invention without departing fromthe scope of the definitions given under compounds of formula (I) andparticular compounds emanated from formula (I) are summarized hereinbelow table encompassing the entirety of the scope of compounds withincompound of formula (I).

Compd No. IUPAC Name 1. 1-methyl-5-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 2.1-methyl-5-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxamide; 3.5-([1,1′-biphenyl]-4-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 4.6-([1,1′-biphenyl]-4-yl)-2-methyl-2H-benzo[d][1,2,3]triazole-4-carboxylic acid; 5.6-([1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-4-carboxylic acid;6. 6-([1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-4- carboxamide;7. 6-([1,1′-biphenyl]-4-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-4-carboxylic acid; 8. 2-methyl-6-(2′-methyl-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]triazole-4-carboxylic acid; 9.1-methyl-6-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-4-carboxylic acid; 10.1-methyl-6-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-4-carboxamide; 11.2-methyl-6-(2′-methyl-[1,1′-biphenyl]-4-yl)-2H- benzo[d][1,2,3]triazole-4-carboxamide; 12.5-(4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-1-methyl-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 13.6-(4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-2-methyl-2H-benzo[d][1,2,3]triazole-4-carboxylic acid; 14.6-(4-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl)-1-methyl-1H-benzo[d][1,2,3]triazole-4-carboxylic acid; 15.1-methyl-5-(3′-(morpholinomethyl)-[1,1′-biphenyl] -4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 16.2-methyl-6-(3′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]triazole-4-carboxylic acid; 17.1-methyl-5-(3′-(pyrrolidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d] [1,2,3]triazole-7-carboxylic acid; 18.1-methyl-6-(3′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-4-carboxylic acid; 19.1-methyl-5-(2,3,5,6-tetrafluoro-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 20.1-methyl-6-(3′-(piperidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-4-carboxylic acid; 21.1-methyl-6-(3′-(pyrrolidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-4-carboxylic acid; 22.1-methyl-5-(3′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 23.2-methyl-6-(3′-(piperidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]triazole-4-carboxylic acid; 24.2-methyl-6-(2,3,5,6-tetrafluoro-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]triazole-4-carboxylic acid; 25.1-methyl-5-(2′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 26.2-methyl-6-(2′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]triazole-4-carboxylic acid; 27.1-methyl-5-(2′-(pyrrolidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 28.2-methyl-6-(2′-(pyrrolidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]triazole-4-carboxylic acid; 29.1-methyl-5-(2′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-3a,7a-dihydro-1H-benzo[d][1,2,3]triazole-7- carboxylicacid; 30. 2-methyl-6-(2′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]triazole-4-carboxylic acid; 31.1-methyl-5-(4′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 32.5-(3′-acetamido-[1,1′-biphenyl]-4-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 33.1-methyl-5-(2,3,5,6-tetrafluoro-3′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 34.1-methyl-5-(2,3,5,6-tetrafluoro-3′-(piperidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid.2,2,2-trifluoroacetic acid; 35.1-methyl-5-(2,3,5,6-tetrafluoro-3′-((4-methylpiperazin-1-yl)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 36.1-methyl-5-(2,3,5,6-tetrafluoro-3′-((isopropylamino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 37.1-methyl-5-(2,3,5,6-tetrafluoro-3′-((methylamino)methyl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid; 38.2-methyl-6-(2,3,5,6-tetrafluoro-3′-(piperidin-1-ylmethyl)-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]triazole-4-carboxylic acid; 39.2-methyl-6-(2,3,5,6-tetrafluoro-3′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-2H-benzo[d][1,2,3]triazole-4-carboxylic acid; and 40.5-(3′-((dimethylamino)methyl)-2,3,5,6-tetrafluoro-[1,1′-biphenyl]-4-yl)-1-methyl-1H-benzo[d][1,2,3]triazole-7- carboxylic acid,or a pharmaceutically acceptable salt thereof or a pharmaceuticallyacceptable regioisomer thereof.

In yet another embodiment, the present invention relates to compounds offormula (I) for use in the treatment of inflammatory disorders andautoimmune diseases or overactive immune response. More preferably, thepresent invention relates to the use of compounds of formula (I) for thetreatment of multiple sclerosis, rheumatoid arthritis and transplantrejection.

Further embodiments of the invention includes use of compounds offormula (I) or pharmaceutically acceptable derivatives, salts andregioisomers thereof, including mixtures thereof in all ratios as amedicament.

Use of compounds as above and pharmaceutically usable derivatives, saltsand regioisomers thereof, including mixtures thereof in all ratios, forthe preparation of a medicament for the treatment and/or prophylaxis ofa dihydroorotate dehydrogenase associated disorder.

Use of compounds as above wherein the dihydroorotate dehydrogenaseassociated disorder is an autoimmune disorder or condition associatedwith an overactive immune response.

Use of compounds as above and pharmaceutically usable derivatives, saltsand regioisomers thereof, including mixtures thereof in all ratios, forthe preparation of a medicament for the treatment and/or prophylaxis ofan immunerogulatory abnomality.

Use of compounds as above wherein the immunoregulatory abnormality ismultiple sclerosis or rheumatoid arthritis.

Use of the compounds as above for the preparation of a medicament forthe treatment and prophylaxis of cancer diseases, inflammatory boweldisease or rheumatoid arthritis.

In a further embodiment, the present invention relates to apharmaceutical formulation comprising at least one compound according toformula (I) and/or pharmaceutically usable derivatives, salts andregioisomers thereof, including mixtures thereof in all ratios, and atleast one further active ingredient.

The present invention further provides a pharmaceutical compositioncomprising at least one compound according to formula (I) and/orpharmaceutically usable derivatives, salts and regioisomers thereof,including mixtures thereof in all ratios, eventually one further activeingredient, and excipients.

The term “pharmaceutically acceptable salt” or “pharmaceuticallyacceptable derivatives” is taken to mean an active ingredient, whichcomprises a compound of the formula (I) in the form of one of its salts,in particular if this salt form imparts improved pharmacokineticproperties on the active ingredient compared with the free form of theactive ingredient or any other salt form of the active ingredient usedearlier. The pharmaceutically acceptable salt form of the activeingredient can also provide this active ingredient for the first timewith a desired pharmacokinetic property which it did not have earlierand can even have a positive influence on the pharmacodynamics of thisactive ingredient with respect to its therapeutic efficacy in the body.

The term “regioisomer” or “regioisomers” refers to the positionalisomers, which is a category of structural isomers, wherein the positionor the substituent changes position on the parent structure. Herein theterm regioisomer without departing from the scope of compound of formula(I) inherently includes all regioisomers either as a pure regioisomer ormixture of two or more regioisomers thereof. Since the pharmaceuticalactivitiy of the regioisomers of the compounds of the present inventionmay differ, it may be desirable to use the regioisomers. In these casesthe regioisomers can be seperated at any of the possible stage either asan intermediate or as an end product by the process well known to theperson skilled in the art or even employed as such in the synthesis. Theregioisomers of the compounds of formula (I) refers to the followingstructures

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

For example, in the case of oral administration as tablet or capsule,the active-ingredient component can be combined with an oral, non-toxicand pharmaceutically acceptable inert excipient, such as, for example,ethanol, glycerol, water and the like. Powders are prepared bycomminuting the compound to a suitable fine size and mixing it with apharmaceutical excipient comminuted in a similar manner, such as, forexample, an edible carbohydrate, such as, for example, starch ormannitol. A flavour, preservative, dispersant and dye may likewise bepresent.

Capsules are produced by preparing a powder mixture as described aboveand filling shaped gelatine shells therewith. Glidants and lubricants,such as, for example, highly disperse silicic acid, talc, magnesiumstearate, calcium stearate or polyethylene glycol in solid form can beadded to the powder mixture before the filling operation. A disintegrantor solubiliser, such as, for example, agar-agar, calcium carbonate orsodium carbonate, may likewise be added in order to improve theavailability of the medica-ment after the capsule has been taken.

In addition, if desired or necessary, suitable binders, lubricants anddisintegrants as well as dyes can likewise be incorporated into themixture. Suitable binders include starch, gelatine, natural sugars, suchas, for example, glucose or beta-lactose, sweeteners made from maize,natural and synthetic rubber, such as, for example, acacia, tragacanthor sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes,and the like. The lubricants used in these dosage forms include sodiumoleate, sodium stearate, magnesium stearate, sodium benzoate, sodiumacetate, sodium chloride and the like. The disintegrants include,without being restricted thereto, starch, methylcellulose, agar,bentonite, xanthan gum and the like. The tablets are formulated by, forexample, preparing a powder mixture, granulating or dry-pressing themixture, adding a lubricant and a disintegrant and pressing the entiremixture to give tablets. A powder mixture is prepared by mixing thecompound comminuted in a suitable manner with a diluent or a base, asdescribed above, and optionally with a binder, such as, for example,carboxymethylcellulose, an alginate, gelatine or polyvinyl-pyrrolidone,a dissolution retardant, such as, for example, paraffin, an absorptionaccelerator, such as, for example, a quaternary salt, and/or anabsorbant, such as, for example, bentonite, kaolin or dicalciumphosphate. The powder mixture can be granulated by wetting it with abinder, such as, for example, syrup, starch paste, acadia mucilage orsolutions of cellulose or polymer materials and pressing it through asieve. As an alternative to granulation, the powder mixture can be runthrough a tableting machine, giving lumps of non-uniform shape which arebroken up to form granules. The granules can be lubricated by additionof stearic acid, a stearate salt, talc or mineral oil in order toprevent sticking to the tablet casting moulds. The lubricated mixture isthen pressed to give tablets. The active ingredients can also becombined with a free-flowing inert excipient and then pressed directlyto give tablets without carrying out the granulation or dry-pressingsteps. A transparent or opaque protective layer consisting of a shellacsealing layer, a layer of sugar or polymer material and a gloss layer ofwax may be present. Dyes can be added to these coatings in order to beable to differentiate between different dosage units.

Oral liquids, such as, for example, solution, syrups and elixirs, can beprepared in the form of dosage units so that a given quantity comprisesa pre-specified amount of the compounds. Syrups can be prepared bydissolving the compounds in an aqueous solution with a suitable flavour,while elixirs are prepared using a non-toxic alcoholic vehicle.Suspensions can be for-mulated by dispersion of the compounds in anon-toxic vehicle. Solubilisers and emulsifiers, such as, for example,ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers,preservatives, flavour additives, such as, for example, peppermint oilor natural sweeteners or saccharin, or other artificial sweeteners andthe like, can likewise be added.

The dosage unit formulations for oral administration can, if desired, beencapsulated in microcapsules. The formulation can also be prepared insuch a way that the release is extended or retarded, such as, forexample, by coating or embedding of particulate material in polymers,wax and the like.

New trisubstituted benzotriazole derivatives of formula (I) and itspharmaceutically acceptable salts and physiologically functionalderivatives thereof and the other active ingredients can also beadministered in the form of liposome delivery systems, such as, forexample, small unilamellar vesicles, large unilamellar vesicles andmultilamellar vesicles. Liposomes can be formed from suitable lipids orphospholipids or both, such as, for example, cholesterol, stearylamineor phosphatidylcholines or the like.

Pharmaceutical formulations adapted for transdermal administration canbe administered as independent plasters for extended, close contact withthe epidermis of the recipient. Thus, for example, the active ingredientcan be delivered from the plaster by iontophoresis, as described ingeneral terms in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical compounds adapted for topical administration can beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For the treatment of the eye or other external tissue, for example mouthand skin, the formulations are preferably applied as topical ointment orcream. In the case of formulation to give an ointment, the activeingredient can be employed either with a paraffinic or a water-misciblecream base. Alternatively, the active ingredient can be formulated togive a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical application to the eyeinclude eye drops, in which the active ingredient is dissolved orsus-pended in a suitable carrier, in particular an aqueous solvent.

Pharmaceutical formulations adapted for topical application in the mouthencompass lozenges, pastilles and mouthwashes.

Pharmaceutical formulations adapted for rectal administration can beadministered in the form of suppositories or enemas.

Pharmaceutical formulations adapted for nasal administration in whichthe carrier substance is a solid comprise a coarse powder having aparticle size, for example, in the range 20-500 microns, which isadministered in the manner in which snuff is taken, i.e. by rapidinhalation via the nasal passages from a container containing the powderheld close to the nose. Suitable formulations for administration asnasal spray or nose drops with a liquid as carrier substance encompassactive-ingredient solutions in water or oil.

Pharmaceutical formulations adapted for administration by inhalationencompass finely particulate dusts or mists, which can be generated byvarious types of pressurised dispensers with aerosols, nebulisers orinsuf-flators.

Pharmaceutical formulations adapted for vaginal administration can beadministered as pessaries, tampons, creams, gels, pastes, foams or sprayformulations. Pharmaceutical formulations adapted for parenteraladministration include aqueous and non-aqueous sterile injectionsolutions comprising antioxidants, buffers, bacteriostatics and solutes,by means of which the formulation is rendered isotonic with the blood ofthe recipient to be treated; and aqueous and non-aqueous sterilesuspensions, which may comprise suspension media and thickeners. Theformulations can be administered in single-dose or multidose containers,for example sealed ampoules and vials, and stored in freeze-dried(lyophilised) state, so that only the addition of the sterile carrierliquid, for example water for injection purposes, immediately before useis necessary.

Injection solutions and suspensions prepared in accordance with therecipe can be prepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavours.

A therapeutically effective amount of a compound of the formula (I) andof the other active ingredient depends on a number of factors,including, for example, the age and weight of the animal, the precisedisease condition which requires treatment, and its severity, the natureof the formulation and the method of administration, and is ultimatelydetermined by the treating doctor or vet. However, an effective amountof a compound is generally in the range from 0.1 to 100 mg/kg of bodyweight of the recipient (mammal) per day and particularly typically inthe range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as an individual doseper day or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound per se.

In yet another embodiment, the present invention relates to a method fortreating a cancer in a subject in need of such treatment comprising thestep of administering to the subject one or more times a therapeuticallyeffective amount of at least one compound or pharmaceutically acceptablesalt thereof disclosed herein.

In yet another embodiment, the present invention relates to a method forinhibiting growth and/or metastasis of tumor cells in a subject,comprising the step of administering to the subject one or more times atherapeutically effective amount of at least one compound orpharmaceutically acceptable salt thereof as disclosed herein.

In yet another embodiment, the present invention relates to a method forinhibiting a dihydrorotate oxygenase enzyme activity in a tumor cell,comprising the step of contacting the tumor cell one or more times witha therapeutically effective amount of at least one compound orpharmaceutically acceptable salt thereof as disclosed herein. In thisembodiment the tumor cells are contacted in vivo, ex vivo or in vitro.

The compounds, pharmaceutically acceptable salts thereof andpharmaceutical formulations and compositions disclosed herein are usefulfor treating cancer in a subject in need of such treatment.Concomittantly, tumor cell growth and/or metastasis or an adihydrorotate oxygenase enzyme activity therein may be inhibited. Thecompounds and pharmaceutical composition may be administered one or moretimes to achieve a therapeutic effect. As is known in the art, theskilled person is well able to determine dose, dosage regimens androutes of administration depending on the condition to be treated andthe subject requiring treatment. Representative examples of a cancerinclude hematological malignancies such as, but not limited to, acutemyeloid leukemia, multiple myeloma, B-prolymphocytic leukemia, and acutelymphoblastic leukemia, and chronic lymphocytic leukemia. Representativeexamples of a cancer include lymphomas such as, but not limited to,Hodgkin's disease, non-Hodgkin's lymphoma, follicular lymphoma, diffuselarge B cell lymphoma, anaplastic large cell lymphoma, and mantle celllymphoma. Representative examples of a cancer include a solid cancersuch as, but not limited to, lung cancer, breast cancer, triple negativebreast cancer, melanoma, glioblastoma, prostate cancer, colon cancer,pancreatic cancer, bone cancer, cancer of the head or neck, skin cancer,cutaneous or intraocular malignant endometrium, carcinoma of the cervix,carcinoma of the vagina, carcinoma of the vulva, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, solid tumours of childhood, lymphocyticlymphoma cancer of the bladder, cancer of the kidney or reter, carcinomaof the renal pelvis, neoplasm of the central nervous system (CNS),primary CNS lymphoma, tumour angiogenesis, spinal axis tumour, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer,squamous cell cancer, T-cell lymphoma, environmentally induced cancersincluding those induced by asbestos, and PTEN mutant cancers.

In a further aspect, the present invention relates to a process forpreparing trisubstituted benzotriazole derivatives of formula (I).

The dihydroorotate dehydrogenase inhibitors according to formula (I) maybe prepared from readily available starting materials using thefollowing general methods and procedures. It will be appreciated thatwhere typical or preferred experimental conditions (i.e. reactiontemperatures, time, moles of reagents, solvents etc.) are given, otherexperimental conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvents used, but such conditions can be determined by the personskilled in the art, using routine optimisation procedures. Moreover, byutilizing the procedures described in detail, one of ordinary skill inthe art can prepare additional compounds of the present inventionclaimed herein. All temperatures are in degrees Celsius (° C.) unlessotherwise noted.

In a further aspect, the compounds of the present invention can alsocontain unnatural proportions of atomic isotopes at one or more of theatoms that constitute such compounds. For example, the present inventionalso embraces isotopically-labeled variants of the present inventionwhich are identical to those recited herein, but for the fact that oneor more atoms of the compound are replaced by an atom having the atomicmass or mass number different from the predominant atomic mass or massnumber usually found in nature for the atom. All isotopes of anyparticular atom or element as specified are contemplated within thescope of the compounds of the invention, and their uses. Exemplaryisotopes that can be incorporated in to compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, chlorine and iodine, such as ²H (“D”), ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I.Isotopically labeled compounds of the present inventions can generallybe prepared by following procedures analogous to those disclosed in theSchemes and/or in the Examples herein below, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.

The following abbreviations refer respectively to the definitions below:

AcOH (Acetic acid), ACN (Acetonitrile), ATP (Adenoside Triphosphate),BSA (Bovine Serum Albumin), CHCl₃ (Chloroform), Cs₂CO₃ (Cesiumcarbonate), DCM (Dichloromethane), DIPEA (di-isopropyl ethylamine), DMSO(Dimethyl Sulfoxide), DMF (N,N-Dimethylformamide), EDCI.HCl(1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride), Et₃N(Triethylamine), EtOAc (Ethyl acetate), EtOH (Ethanol), HOBT(Hydroxybenzotriazole), HCl (Hydrogen chloride), K₂CO₃ (PotassiumCarbonate), min (minute), MeOH (Methanol), MeI (Methyl Iodide), MgSO₄(Magnesium sulfate), NH₄Cl (Ammonium chloride), NH₄(CO₃)₂ (ammoniumcarbonate), Pd(dppf)₂Cl₂([1,1-bis(diphenylphosphino)-ferrocene]dichloropalladium (II)), NaH (Sodium hydride), NaNO₂(Sodium nitrite), NaHCO₃ (Sodium bicarbonate), PetEther (Petroleumether), PBS (Phosphate Buffered Saline), RT—room temperature (25° C.-35°C.), TEA (Triethyl amine), TFA (Trifluoroacetic acid), THF(Tetrahydrofuran), t-BuOK (Potassium tert-butoxide), TMSI(Trimethylsilyl iodide), TLC (Thin Layer Chromatography), H₂O—Water;mL—Milli Liter; hr/h—Hour; N—Normality; M—Molarity; s—Singlet;d—Doublet; t—Triplet; m—Multiplet; ¹HNMR—Proton nuclear magneticresonance; MS—Mass spectroscopy; LC—Liquid chromatography; HPLC—HighPerformance Liquid Chromatography, J—Coupling Constant; ¹H—Proton;MHz—Mega Hertz (frequency); Hz—Hertz; ppm—Parts per million; bs—Broadsinglet; ES—Electro spray; Conc.—Concentrated; g—Gram; mmol or mM—Millimolar; μM —Micro molar; nM—Nano molar; UV—Ultraviolet; ° C.—degreeCelsius, M⁺—Molecular ion, %—Percentage; μ—Micron; and δ—Delta;anh.—Anhydrous; pH—potential of Hydrogen;

Another embodiment of the present invention provides methods useful formaking the compounds of formula (I) are set forth in the Examples belowand generalized in Scheme-I. One of skill in the art will recognize thatScheme I can be adapted to produce the compounds of formula (I) andpharmaceutically accepted salts of compounds of formula (I) according tothe present invention. Wherein all symbols/variables are as definedearlier unless otherwise stated.

The process is represented by Scheme-I:

Compounds of the invention may be prepared using the synthetictransformations illustrated in Scheme-I. Starting materials arecommercially available, may be prepared by the procedures describedherein, by literature procedures, or by procedures that would be wellknown to one skilled in the art of organic chemistry. Starting material5-substituted methyl 2,3-diamino-benzoate is prepared by the proceduresdescribed in WO2010115736A2.

Step-a: Compound-i is reacted with sodium nitrite in acidic medium usingGeneral Procedure-A to afford the compound-ii.

Step-b: Compound-ii is further subjected to N-alkylation using methyliodide in basic conditions such as those described in GeneralProcedure-B to afford the compounds of formula-iii.

Step-c: The compounds of formula-iii are reacted with bispinacolatediboran in basic medium in presence of suitable palladium catalyst usingGeneral Procedure-C to afford the compounds of formula-iv.

Step-d: The compounds of formula-iv treated with substituted aryl halidein presence of suitable palladium catalyst using the conditions such asthose described in General Procedure-D to afford the compounds offormula-v.

Step-e: Alternatively the compounds of formula-v can be prepared fromthe compounds of formula-iii by using appropriate boronic acids, atsuitable conditions such as those described in General Procedure-D.

Step-f: The resultant compounds of formula-v under goes ester hydrolysisunder basic conditions such as those described in General Procedure-F toafford compounds of formula (I) (wherein R₃═OH).

Step-g: Carboxylic acids of formula (I) was treated with ammoniumchloride using the conditions that are described in General procedure-Gto afford the respective compounds of formula (I) (wherein R₃═NH₂).

If the above set of general synthetic methods is not applicable toobtain compounds according to formula (I) and/or necessary intermediatesfor the synthesis of compounds of formula (I), suitable methods ofpreparation known by a person skilled in the art should be used. Ingeneral, the synthesis pathways for any individual compound of formula(I) will depend on the specific substituents of each molecule and uponthe ready availability of intermediates necessary; again such factorsbeing appreciated by those of ordinary skill in the art.

Compounds of this invention can be isolated in association with solventmolecules by crystallization from evaporation of an appropriate solvent.The pharmaceutically acceptable acid addition salts of the compounds offormula (I), which contain a basic center, may be prepared in aconventional manner. For example, a solution of the free base may betreated with a suitable acid, either neat or in a suitable solution, andthe resulting salt isolated either by filtration or by evaporation undervacuum of the reaction solvent. Pharmaceutically acceptable baseaddition salts may be obtained in an analogous manner by treating asolution of compound of formula (I) with a suitable base. Both types ofsalts may be formed or interconverted using ion-exchange resintechniques.

Although the invention is illustrated by certain of the followingexamples, it is not to be construed as being limited thereby; butrather, the invention encompasses the generic area as hereinbeforedisclosed. Various modifications and embodiments can be made withoutdeparting from the spirit and scope thereof.

EXAMPLES General

The MS data provided in the examples described below were obtained asfollowed: Mass spectrum: LC/MS Waters ZMD (ESI) or a Waters Acquity SQD(ESI).

The NMR data provided in the examples described below were obtained asfollowed: ¹H-NMR: Bruker DPX-300 MHz or a Bruker DPX 400 MHz.

The HPLC data provided in the examples described below were obtained asfollowed. Condition A: Column Waters Xbridge™ C₈ 50 mm×4.6 mm at a flowof 2 mL/min; 8 min gradient from 0.1% TFA in H₂O to 0.07% TFA in CH₃CN.

Condition B: C18 BDS (4.6×250) mm, SC\244 at a flow of 0.7 mL/min; 10min gradient from 0.1% TFA in H₂O to CH₃CN.

Preparative HPLC conditions: Column-Zorbax Eclipse XDB C18 PrepHT(150×21.2 mm, 50; Mobile Phase: (A) 0.01% TFA or 0.1% TFA; (B) ACN orACN: MeOH (1:1); Flow: 20 ml/min.

Preparative HPLC purifications were performed with a mass directedautopurification Fractionlynx from Waters equipped with a Sunfire PrepC18 OBD column 19×100 mm 5 μm, unless otherwise reported. All HPLCpurifications were performed with a gradient of ACN/H₂O or ACN/H₂O/HCOOH(0.1%).

The compounds of invention have been named according to the standardsused in the programACD/Name Batch from “Advanced Chemistry DevelopmentInc., ACD/Labs (7.00 Release)”. Product version: 7.10 build: 15 Sep.2003.

The procedure for the compounds of formula (I) are detailed herein belowthe general procedures including the general synthesis of variousintermediates involved in process of manufacture of the compoundsaccording to the present invention.

General Procedure-A: Preparation of Substituted [1,2,3]benzotriazoles

To a flask containing 6-substituted or substituted diamino ester (1-3equiv) in acetic acid is stirred for 10-20 min preferably 10 minfollowed by the addition of (sodium nitrite, potassium nitritepreferably sodium nitrite) (2.5-3.5 preferably 2.5 equiv) in water. Thereaction mixture stirred for 1-2 h. preferably 1 h at RT. The separatedsolid is collected by filtration and dried under vacuum to obtain thetarget products.

Illustrative Example of General Procedure-A Preparation # A.1: Synthesisof methyl 6-bromo-1H-benzo[d] [1,2,3]triazole-4-carboxylate:

A solution of methyl 2,3-diamino-5-bromobenzoate (1.0 g, 4.08 mmol)(Ref:WO2010/115736 A2) in acetic acid (15 mL) was stirred for 10 min atRT. Sodium nitrite (0.309 g, 4.48 mmol) in water (2 mL) was added andthe reaction mixture stirred for about 30 min at RT. The precipitatedsolid was filtered, washed with water and dried under vacuum to afforddesired product (0.8 g, 77%); ¹H NMR (400 MHz, DMSO-d6):δ16.19 (s, 1H),8.70 (s, 1H), 8.14 (s, 1H), 3.99 (s, 3H) and LC-MS m/z: 258 (M+H)⁺.

General Procedure-B: N-alkylation of substituted benzotrizoles

To a stirred solution of substituted Benzotriazoles-carboxylatederivative (1 equiv) in an organic solvent (such as DMF, THF, Dioxanepreferably DMF) is added a suitable base (such as K₂CO₃, CS₂CO₃, NaHetc. preferably K₂CO₃ 2 to 5 equivalents preferably 2. equiv) followedby alkyl halide (2 to 5 equiv, preferably 3 equiv). The reaction mixturestirred RT for about 1 to 10 h (preferably 3 h). The reaction mixture ispoured into ice cold water and the separated solid is collected byfiltration and dried under vacuum. The regioisomers were separated bycolumn chromatography to obtain the desired products.

Illustrative Example of General Procedure-B Preparation # B.1: Synthesisof methyl 5-bromo-1-methyl-1H-benzo[d] [1,2,3]triazole-7-carboxylate,methyl 6-bromo-2-methyl-2H-benzo[d] [1,2,3]triazole-4-carboxylate andmethyl 6-bromo-1-methyl-1H-benzo[d] [1,2,3]triazole-4-carboxylate:

To a stirred solution of methyl 6-bromo-1H-benzo[d][1,2,3]triazole-4-carboxylate (4.5 g, 17.5 mmol, preparation #A.1) inDMF (25 mL) was added potassium carbonate (4.85 g, 35.15 mmol) followedby methyl iodide (7.48 g, 52.73 mmol). The reaction mixture was stirredat RT for 1 h. The reaction mixture was quenched with ice cold water(100 mL) and the separated solid was collected by filtration, driedunder vacuum. The obtained crude compound was purified by columnchromatography over silica gel (100-200 mesh) using 10% ethyl acetate inhexane to get the Isomer-I (B.1.a) (1.9 g); ¹H NMR (400 MHz, CDCl₃)δ8.40 (s, 1H), 8.22 (s, 1H), 4.57 (s, 3H), 4.01 (s, 3H) and LC-MS m/z:272 (M+2)⁺; 15-20% ethyl acetate in hexane to get the Isomer-II (B.1.b)(1.4 g); ¹H NMR (400 MHz, CDCl₃) δ8.26 (s, 1H), 8.23 (s, 1H), 4.58 (s,3H), 4.04 (s, 3H) and LC-MS m/z: 272.0 (M+2)⁺; 20-25% ethyl acetate inhexane to get the Isomer-III (B.1.c) (1.0 g); ¹H NMR (400 MHz, DMSO-d₆):δ8.67 (s, 1H), 8.13 (s, 1H), 4.45 (s, 3H), 3.96 (s, 3H) and LC-MS m/z:272.0 (M+2)⁺.

General Procedure-C: Preparation of Boronic Ester

A mixture of aryl halo derivative (1.0 to 3.0 equiv, preferably 1.0equiv), suitable inorganic base (such as KOAC or Na₂CO₃ or K₂CO₃ orCs₂CO₃ preferably KOAC), bispinacolate diborane (1.0 to 3.0 equiv,preferably 1.1 equiv) in dioxane is degased with nitrogen for about 10to 15 min and added [1, 1-bis (diphenylphosphino)-ferrocene]dichloropalladium (II) (0.001 to 0.010 equiv, preferably 0.05 equiv).The reaction mixture is stirred at reflux temperature under nitrogen forabout 3 h to 12 h (preferably about 6 h). The reaction mixture is cooledto RT and evaporated to dryness under reduced pressure. The residueobtained is re-dissolved in EtOAc, washed successively with water andbrine solution. The organic solution is dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The product is purified bycrystallization or trituration from an appropriate solvent or solventsor by preparative HPLC or flash chromatography.

Illustrative Example of General Procedure-C Preparation # C.1: Synthesisof methyl1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylate:

A mixture of methyl 5-bromo-1-methyl-1H-benzo[d][1,2,3]triazole-7-carboxylate (1.0 g, 3.7 mmol, preparation # B.1.a),potassium acetate (0.627 g, 5.92 mmol), bispinacolate diborane (0.93 g,3.7 mmol) in dioxane (60 mL) was degased with nitrogen for about 15 minand added [1, 1-bis (diphenylphosphino)-ferrocene]dichloropalladium(II)(0.151 g, 0.018 mmol). The reaction mixture was stirred at refluxtemperature for 6 h under nitrogen. The reaction mixture was cooled toRT and evaporated to dryness under reduced pressure. The residueobtained was re-dissolved in EtOAc, washed successively with water andbrine solution and concentrated. The obtained crude compound waspurified by column chromatography over silica gel (60-120 mesh) using30% ethyl acetate in hexane to get the desired product (0.9 g, 77%); ¹HNMR (400 MHz, DMSO-d6): δ8.46 (s, 1H), 8.31 (s, 1H), 4.59 (s, 3H), 3.94(s, 3H), 1.35 (s, 12H) and LC-MS m/z=318.2 (M+H)⁺.

Other compounds synthesized using General procedure C are described inTable C.1

General Procedure-D: Suzuki Reaction

A mixture of acetonitrile and water (8:2) is degased with nitrogen forabout 10 to 15 min then added suitable base (such as Na₂CO₃ or K₂CO₃ orCs₂CO₃ preferably Na₂CO₃) followed by aryl bromo derivative (1.0 to 3.0equiv, preferably 1.0 equiv) and appropriate boronic acid (1.0 to 3.0equiv, preferably 1.5 equiv). The reaction mixture is again degassed for15 min and finally added [1, 1-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (0.001 to 0.010 equiv, preferably 0.05 equiv) isadded. The reaction mixture is stirred at reflux temperature undernitrogen for about 3 h to 12 h (preferably about 4 h). The reactionmixture is cooled to RT and evaporated to dryness under reducedpressure. The obtained residue is re-dissolved in EtOAc, washedsuccessively with water and brine solution. The organic solution isdried over Na₂SO₄, filtered and concentrated under reduced pressure. Theproduct is purified by crystallization or trituration from anappropriate solvent or solvents or by preparative HPLC or flashchromatography.

Illustrative Example of General Procedure-D Preparation # D.1: Synthesisof methyl 1-methyl-5-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo [d][1,2,3]triazole-7-carboxylate:

A mixture of acetonitrile (80 mL) and water (15 mL) was degassed withnitrogen for 10 min. Sodium carbonate (2.74 g, 25.9 mmol) was addedfollowed by methyl5-bromo-1-methyl-1H-benzo[d][1,2,3]triazole-7-carboxylate (3.5 g, 12.9mmol) and4,4,5,5-tetramethyl-2-(2′-methyl-[1,1′-biphenyl]-4-yl)-1,3,2-dioxaborolane(3.81 g, 12.0 mmol) (C.1.5). The reaction mixture was again degassed for15 min. Finally[1,1-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) (0.526 g,0.64 mmol) was added. The reaction mixture was stirred at refluxtemperature for 5 h under nitrogen. The reaction mixture was cooled toRT and evaporated to dryness under reduced pressure. The obtainedresidue was re-dissolved in EtOAc, washed successively with water andbrine solution and concentrated. The obtained crude compound waspurified by column chromatography over silica gel (60-120 mesh) using30% ethyl acetate in hexane to get the desired product (3.6 g, 77%); ¹HNMR (400 MHz, CDCl₃): δ8.52 (s, 1H), 8.31 (s, 1H), 7.76-7.74 (d, J=8.0Hz, 2H), 7.48-7.46 (d, J=7.6, 2H), 7.31-7.28 (m, 4H), 4.63 (s, 3H), 4.08(s, 3H), 2.34 (s, 3H) and LC-MS m/z=358.2 (M+H)⁺.

Other compounds synthesized using General procedure D are described inTable D.1.

General Procedure-E: Reductive Amination

A mixture of appropriate aldehyde and amine in organic solvent (such asDCM, THF, ACN, DMF, DCE, or Dioxane) is stirred at room temperature for30 min to 4 hrs. The resulting reaction mixture is cooled to 0° C. andadded reducing agent such as sodium triacetoxyborohydride in smallportions followed by catalytic amount of acetic acid. The resultingreaction mixture is stirred at room temperature for 2-4 hrs. Theprogress of the reaction is monitored by TLC, and the reaction mixtureis quenched with an aq. solution of sodium bicarbonate. Further it isextracted with ethyl acetate, the combined organic layers are dried oversodium sulphate and concentrated under vacuum to affrord the targetcompound. Optionally, the target compound can be purified bycrystallization or trituration from an appropriate solvent or solvents,or by preparative HPLC or flash chromatography.

Illustrative Example of General Procedure-E Preparation #E. 1: Synthesisof methyl 1-methyl-5-(2′-(morpholinomethyl)-[1,1′-biphenyl]-4-yl)-1H-benzo [d] [1,2,3]triazole-7-carboxylate:

A solution of methyl 5-(2′-formyl-[1,1′-biphenyl]-4-yl)-1-methyl-1H-benzo [d][1,2,3]triazole-7-carboxylate (0.300 g, 0.8 mmol, D.1.8) and morpholine(0.070 g, 0.8 mmol) in DCE (15 mL) was stirred for 30 min at roomtemperature. The reaction mixture was cooled to 0° C., added sodiumtriacetoxy borohydride (0.342 g, 1.6 mmol) followed by acetic acid (0.2mL). The reaction mixture was stirred for 2 h at room temperature. Thereaction mixture was quenched with an aq. solution of sodium bicarbonate(50 mL). It was extracted with ethyl acetate (3×50 mL), combined organiclayers were dried over sodium sulphate and concentrated under reducedpressure. The obtained crude was taken to next step without purification(0.200 g); ¹H NMR (400 MHz, DMSO-d₆): δ 8.69 (s, 1H), 8.696 (s, 1H),8.424-8.422 (d, J=8 Hz, 2H), 7.912-7.891 (d, J=8 Hz, 2H), 7.607 (m, 1H),7.531-7.324 (m, 3H), 4.50 (s, 3H), 4.0 (s, 3H), 3.560 (m, 4H), 3.55 (s,2H), 3.308 (m, 4H) and LC-MS m/z=443.3 (M+H)⁺.

General Procedure-F: Ester Hydrolysis

To a flask containing an appropriate alkyl ester in an aqueous organicsolvent (such as THF or methanol, 1,4 Dioxane preferably 1,4 Dioxane) isadded 1.5 equiv. of aqueous sodium hydroxide solution and the reactionmixture is refluxed for 1-8 h. (preferably 4 h). Completion of thereaction is monitored by TLC. Excess solvent is removed under vacuum andthe solution is acidified with 10% HCl solution. The separated solid iscollected by filtration and dried under vacuum to obtain the targetcarboxylic acid derivative. Optionally, the target compound can bepurified by crystallization or trituration from an appropriate solventor solvents, or by preparative HPLC or flash chromatography.

Illustrative Example of General Procedure-F Example # 1: Synthesis of1-methyl-5-(2′-methyl-[1,1′-biphenyl]-4- yl)-1H-benzo [d][1,2,3]triazole-7-carboxylic acid (Compound-1):

To a stirred solution of methyl 1-methyl-5-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d] [1,2,3]triazole-7-carboxylate (1.2 g, 3.361 mmol,D.1) in 1,4 Dioxane (15 mL) was added aq. 2N NaOH (15 mL). The reactionmixture was refluxed for 4 h. After the completion of the reaction, thereaction mixture was cooled to room temperature, excess solvent wasremoved under reduced pressure and the solution was acidified with 10%HCl solution (pH-2). The separated solid is collected by filtration anddried under vacuum to get the titled compound as an off white solid (1.1g, 95%); ¹H NMR (400 MHz, DMSO-d6): δ 13.35 (bs, 1H), 8.52 (s, 1H), 8.38(s, 1H), 7.89-7.87 (d, J=8.0 Hz, 2H), 7.51-7.49 (d, J=8.4 Hz, 2H),7.32-7.25 (m, 4H), 4.58 (s, 3H) 2.30 (s, 3H) and LC-MS m/z=344.1 (M+H)⁺.

General Procedure-G: Amide Formation

To a flask containing appropriate carboxylic acid derivative (1.0 equiv)in an organic solvent (such as DMF, THF or CH₂Cl₂) is added EDCI.HCl(1.5 equiv), HOBT (1.5 equiv) and N-ethyl-N-isopropylpropan-2-amine (3equiv). After stirring for about 10 min at approximately 25° C., theappropriate amine (1.5 equiv) is added and the reaction is stirred foran additional 8-12 h (preferably 12 h.). The separated solid uponaddition of water is collected by filtration and dried under vacuum toobtain the amide derivative. Optionally, the obtained compound can bepurified by crystallization or trituration from an appropriate solventor solvents, or by preparative HPLC or flash chromatography.

Illustrative Example of General Procedure-G Example #2: Synthesis of1-methyl-5-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo [d][1,2,3]triazole-7-carboxamide (Compound-2):

To a flask containing a1-methyl-5-(2′-methyl-[1,1′-biphenyl]-4-yl)-1H-benzo[d][1,2,3]triazole-7-carboxylic acid (0.150 g, 0.43 mmol, Compound-1) inDMF (3 mL) was added EDCI.HCl (0.100 g, 0.52 mmol), HOBT (0.070 g, 0.52mmol) and N-ethyl-N-isopropylpropan-2-amine (0.168 g, 1.31 mmol) .Themixture was stirred at about 25° C. for approximately 10 min and wasadded ammonium chloride (0.070 g, 1.31 mmol). The reaction was thenstirred for about additional 12 h and quenched with water (50 mL). Theseparated solid was collected by filtration and dried under vacuum toget the desired compound as an off white solid (0.08 g, 53%); ¹H NMR(400 MHz, DMSO-d6): δ8.47 (s, 1H), 8.37 (s, 1H), 8.05 (s, 1H), 8.00 (s,1H), 7.90-7.88 (d, J=8.0 Hz, 2H), 7.51-7.49 (d, J=7.6 Hz, 2H), 7.35-7.27(m, 4H), 4.61 (s, 3H), 2.30 (s, 3H) and LC-MS m/z=343.2 (M+H)⁺.

The below intermediates were prepared by procedure similar to the onedescribed in General procedure-C with appropriate variations inreactants, quantities of reagents and reaction conditions. Thephysiochemical characteristics of the compounds are summarized hereinbelow table-C.1.

TABLE C.1. Reactant/ Intermediate Int No. Source Structure Analyticaldata C.1.1

¹H NMR (400 MHz, DMSO-d6): δ 8.46 (s, 1H), 8.31 (s, 1H), 4.59 (s, 3H),3.94 (s, 3H), 1.35 (s, 12H) and LC-MS m/z = 318.2 (M + H)⁺. C.1.2

¹H NMR (400 MHz, DMSO-d6): δ 7.80- 7.78 (d, J = 8 Hz, 2H), 7.27-7.25 (d,J = 8 Hz, 2H), 5.80 (m, 2H), 1.96 (s, 6H), 1.31 (s, 12H) and LC-MS m/z =298.2 (M + H)⁺. C.1.3

  JOC, 2008, vol. 73, # 14 p. 5558-65

¹H NMR (400 MHz, DMSO-d6): δ 9.88 (s, 1H), 7.94 (d, J = 7.2 Hz, 1H),7.81-7.75 (m, 3H), 7.63-7.45 (m, 4H), 1.32 (s, 12H) and LC-MS m/z =298.2 (M + H)⁺. C.1.4

  EP1970377

¹H NMR (400 MHz, DMSO-d6): δ 10.04 (s, 1H), 7.92-7.91 (d, J = 4 Hz, 1H),7.83- 7.58 (m, 4H), 7.41-7.33 (m, 2H), 2.06 (s, 3H), 1.31 (s, 12H) andLC-MS m/z = 338.2 (M + H)⁺. C.1.5

  Synlett, 2005, # 11, p. 1775- 78.

¹H NMR (400 MHz, CDCl₃): δ 7.87-7.85 (d, J = 8 Hz, 2H), 7.35-7.33 (d, J= 8 Hz, 2H), 7.26-7.24 (m, 4H), 2.26 (s, 3H), 1.36 (s, 12H) and LC-MSm/z = 295.2 (M + H)⁺.

The below intermediates were prepared by procedure similar to the onedescribed in General procedure-D with appropriate variations inreactants, quantities of reagents and reaction conditions. Thephysiochemical characteristics of the compounds are summarized hereinbelow table-D.1.

TABLE D.1. Reactant/ Int No. Source Intermediate Structure Analyticaldata D.1.1

¹H NMR (400 MHz, CDCl₃): δ 8.50 (s, 1H), 8.30 (s, 1H), 7.79-7.65 (m,6H), 7.48-7.38 (m, 3H), 4.62 (s, 3H), 4.08 (s, 3H) and LC-MS m/z = 344(M + H)⁺. D.1.2

¹H NMR (400 MHz, CDCl₃): δ 8.48-8.46 (d, J = 8.8 Hz, 2H), 7.78- 7.65 (m,6H), 7.48-7.37 (m, 3H), 4.62 (s, 3H), 4.04 (s, 3H) and LC- MS m/z = 344(M + H)⁺. D.1.3

LC-MS m/z = 344 (M + H)⁺. D.1.4

¹H NMR (400 MHz, DMSO-d6): δ 16.05 (s, 1H), 8.73 (s, 1H), 8.42 (s, 1H),7.94-7.92 (d, J = 8 Hz, 2H), 7.84-7.82 (d, J = 8 Hz, 2H), 7.76-7.74 (m,2H), 7.53-7.38 (m, 3H), 4.03 (s, 3H) and LC-MS m/z = 330.2 (M + H)⁺.D.1.5

¹H NMR (400 MHz, DMSO-d6): δ 8.69 (s, 1H), 8.41 (s, 1H), 7.96-7.94 (d, J= 8 Hz, 2H), 7.41-7.39 (d, J = 8 Hz, 2H), 5.8 (s, 2H), 4.50 (s, 3H),4.00 (s, 3H), 2.02 (s, 6H) and LC- MS m/z = 361.2 (M + H)⁺. D.1.6

¹H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 1H), 8.40 (s, 1H), 7.95-7.93 (d, J= 8 Hz, 2H), 7.41-7.39 (d, J = 8 Hz, 2H), 5.83 (s, 2H), 4.59 (s, 3H),4.00 (s, 3H), 2.02 (s, 6H) and LC- MS m/z = 361.1 (M + H)⁺. D.1.7

¹H NMR (400 MHz, DMSO-d6): δ 8.57 (s, 1H), 8.39 (s, 1H), 7.95-7.93 (d, J= 8 Hz, 2H), 7.41-7.39 (d, J = 8 Hz, 2H), 5.83 (s, 2H), 4.59 (s, 3H),4.00 (s, 3H), 2.02 (s, 6H) and LC- MS m/z = 361.2 (M + H)⁺. D.1.8

¹H NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 8.71 (s, 1H), 8.41 (s, 1H),8.29 (s, 1H), 8.12-8.10 (d, J = 8 Hz, 1H), 7.994-7.905 (m, 5H), 7.75-7.72 (m, 1H), 4.49 (s, 3H), 4.00 (s, 3H) and LC-MS m/z = 372.1 (M + H)⁺.D.1.9

¹H NMR (400 MHz, DMSO-d6): δ 10.13 (s, 1H), 8.60 (s, 1H), 8.42 (s, 1H),8.3 (s, 1H), 8.13-8.11 (d, J = 8 Hz, 1H), 7.99-7.92 (m, 5H), 7.76- 7.72(m, 1H), 4.60 (s, 3H), 4.01 (s, 3H) and LC-MS m/z = 372.2 (M + H)⁺.D.1.10

¹H NMR (400 MHz, DMSO-d6): δ 10.14 (s, 1H), 8.57 (s, 1H), 8.32 (s, 1H),8.31 (s, 1H), 8.14-8.12 (d, J = 8 Hz, 1H), 8.031-7.93 (m, 5H), 7.77-7.73 (m, 1H), 4.43 (s, 3H), 4.01 (s, 3H) and LC-MS m/z = 372.2 (M + H)⁺.D.1.11

¹H NMR (400 MHz, DMSO-d6): δ 10.08 (s, 1H), 8.72 (s, 1H), 8.42 (s, 1H),8.04-7.92 (m, 8H), 4.49 (s, 3H), 4.00 (s, 3H) and LC-MS m/z = 372.1 (M +H)⁺. D.1.12

¹H NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1H), 8.73 (s, 1H), 7.99-7.97 (m,3H), 7.82-7.80 (m, 1H), 7.784- 7.61 (m, 4H), 4.50 (s, 3H), 4.00 (s, 3H)and LC-MS m/z = 372.1 (M + H)⁺. D.1.13

¹H NMR (400 MHz, DMSO-d6): δ 9.98 (s, 1H), 8.61 (s, 1H), 8.43 (s, 1H),7.98-7.96 (m, 3H), 7.80-7.79 (m, 1H), 7.64-7.59 (m, 4H), 4.60 (s, 3H),3.98 (s, 3H) and LC-MS m/z = 372.2 (M + H)⁺. D.1.14

  Organic Letters, 2009,

¹H NMR (400 MHz, DMSO-d6): δ 8.30-8.28 (m, 2H), 7.54-7.50 (m, 5H), 4.65(s, 3H), 4.07 (s, 3H) and LC-MS m/z = 416.1 (M + H)⁺. vol. 11, # 15, p.3346-49. D.1.15

  Organic Letters, 2009,

LC-MS m/z = 416.1 (M + H)⁺. vol. 11, # 15 p. 3346-49. D.1.16

¹H NMR (400 MHz, DMSO-d6): δ 10.12 (s, 1H), 8.67 (s, 1H), 8.26 (s, 1H),8.13-8.11 (m, 2H), 7.96-7.83 (m, 2H), 4.53 (s, 3H), 4.0 (s, 3H); LC-MSm/z = 444.1 (M + H)⁺. D.1.17

¹H NMR (400 MHz, DMSO-d6): δ 8.52 (s, 1H), 8.37 (s, 1H), 4.64 (s, 3H),4.10 (s, 3H); LC-MS m/z = 418 (M + H)⁺.

The below compounds were prepared by procedure similar to the onedescribed in General procedures-E, F and G with appropriate variationsin reactants, quantities of reagents and reaction conditions. Thephysiochemical characteristics of the compounds are summarized hereinbelow table.

Comp General No. Structure Procedure Analytical data  3

F ¹H NMR (400 MHz, DMSO-d6): δ 13.34 (bs, 1H), 8.53 (s, 1H), 8.38 (s,1H), 7.93- 7.91 (d, J = 8.4 Hz, 2H), 7.84-7.82 (d, J = 8.8 Hz, 2H),7.76-7.74 (d, J = 7.6 Hz, 2H), 7.53-7.40 (m, 3H), 4.58 (s, 3H) and LC-MSm/z = 330.1 (M + H)⁺.  4

F ¹H NMR (400 MHz, DMSO-d6): δ 13.34 (bs, 1H), 8.51 (s, 1H), 8.28 (s,1H), 7.97- 7.95 (d, J = 8.4 Hz, 2H), 7.87-7.85 (d, J = 8.4 Hz, 2H),7.78-7.76 (d, J = 7.6 Hz, 2H), 7.53-7.41 (m, 3H), 4.42 (s, 3H) and LC-MSm/z = 330.1 (M + H)⁺.  5

F ¹H NMR (400 MHz, DMSO-d6): δ 13.34 (bs, 1H), 8.64 (s, 1H), 8.43 (s,1H), 7.92 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.76 (d, J =7.2 Hz, 2H), 7.55-7.41 (m, 3H) and LC-MS m/z = 316.1 (M + H)⁺.  6

F and G ¹H NMR (400 MHz, DMSO-d6): δ 15.9 (bs, 1H), 8.61 (s, 1H), 8.48(s, 1H), 8.41 (s, 1H), 7.98 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8 Hz, 2H),7.77-7.75 (m 3H), 7.52-7.38 (m, 3H) and LC-MS m/z = 315.1 (M + H)⁺.  7

F ¹H NMR (400 MHz, DMSO-d6): δ 13.9 (bs, 1H), 8.63 (s, 1H), 8.39 (s,1H), 7.94-7.92 (d, J = 8.4 Hz, 2H), 7.83-7.81 (d, J = 8.4 Hz, 2H),7.76-7.74 (d, J = 7.2 Hz, 2H), 7.52-7.40 (m, 3H), 4.52 (s, 3H) and LC-MSm/z = 330.1 (M + H)⁺.  8

F ¹H NMR (400 MHz, DMSO-d6): δ 13.39 (bs, 1H), 8.50 (s, 1H), 8.28 (s,1H), 7.93- 7.91 (d, J = 7.6 Hz, 2H), 7.54-7.52 (d, J = 8.4 Hz, 2H),7.35-7.27 (m, 4H), 4.41 (s, 3H) 2.30 (s, 3H) and LC-MS m/z = 344.1 (M +H)⁺.  9

F ¹H NMR (400 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.40 (s, 1H), 7.90-7.88 (d,J = 8.4 Hz, 2H), 7.51-7.49 (d, J = 7.6 Hz, 2H), 7.32-7.27 (m, 4H), 4.52(s, 3H) 2.30 (s, 3H) and LC- MS m/z = 344.2 (M + H)⁺. 10

G ¹H NMR (400 MHz, DMSO-d6): δ 8.54 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H),8.14 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H),7.34-7.28 (m, 4H), 4.45 (s, 3H), 2.30 (s, 3H) and LC-MS m/z = 343.2 (M +H)⁺. 11

F and G ¹H NMR (400 MHz, DMSO-d6): δ 8.54 (s, 1H), 8.49 (s, 1H), 8.34(s, 1H), 8.14 (s, 1H), 7.93-7.91 (d, J = 8.4 Hz, 2H), 7.54-7.52 (d, J =8.4 Hz, 2H), 7.34-7.28 (m, 4H), 4.45 (s, 3H), 2.30 (s, 3H) and LC-MS m/z= 343.2 (M + H)⁺. 12

F ¹H NMR (400 MHz, DMSO-d6): δ 13.8 (bs, 1H), 8.67 (s, 1H), 8.40 (s,1H), 7.97 (d, J = 8 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 5.83 (s, 2H),4.52 (s, 3H), 2.03 (s, 6H) and LC-MS m/z: 347.2 (M + H)⁺. 13

F ¹H NMR (400 MHz, DMSO-d6): δ 13.38 (bs, 1H), 8.56 (s, 1H), 8.37 (s,1H), 7.96 (d, J = 8 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 5.83 (s, 2H),4.58 (s, 3H), 2.03 (s, 6H) and LC- MS m/z: 347.2 (M + H)⁺. 14

F ¹H NMR (400 MHz, DMSO-d6): δ 13.38 (bs, 1H), 8.53 (s, 1H), 8.27 (s,1H), 7.98 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 5.84 (s, 2H),4.41 (s, 3H), 2.03 (s, 6H) and LC- MS m/z: 347.2 (M + H)⁺. 15

E and F ¹H NMR (400 MHz, DMSO-d6): δ 13.38 (bs, 1H), 8.62 (s, 1H), 8.38(s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.67- 7.63(m, 3H), 7.48-7.44 (m, 1H), 7.35 (d, J = 8 Hz, 1H), 4.5 (s, 3H), 3.61(m, 6H), 2.43 (m, 4H) and LC-MS m/z: 429.2 (M + H)⁺. 16

E and F ¹H NMR (400 MHz, DMSO-d6): δ 13.38 (bs, 1H), 8.52 (s, 1H), 8.38(s, 1H), 7.93 (d, J = 8 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.67- 7.64(m, 2H), 7.48-7.45 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 8 Hz, 1H), 4.58 (s,3H), 3.60 (m, 6H), 2.43 (m, 4H) and LC-MS m/z: 429.2 (M + H)⁺. 17

E and F ¹H NMR (400 MHz, DMSO-d6): δ 11.82 (bs, 1H), 8.20 (s, 1H), 8.06(s, 1H), 7.83- 7.61 (m, 6H), 7.44 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 7.6Hz, 1H), 4.54 (s, 3H), 3.74 (s, 2H), 1.74 (m, 4H), 1.23 (m, 4H) andLC-MS m/z: 413.2 (M + H)⁺. 18

E and F ¹H NMR (400 MHz, DMSO-d6): δ 13.2 (bs, 1H), 8.49 (s, 1H), 8.27(s, 1H), 7.96 (d, J = 8 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H), 7.67- 7.64(m, 2H), 7.48-7.46 (m, 1H), 7.44-7.34 (m, 1H), 4.44 (s, 3H), 3.60-3.57(m, 6H), 2.41 (m, 4H) and LC-MS m/z = 429.2 (M + H)⁺. 19

F ¹H NMR (400 MHz, DMSO-d6): δ 13.8 (bs, 1H), 8.60 (s, 1H), 7.59 (s,1H), 7.65-755. (m, 5H), 4.45 (s, 3H) and LC-MS m/z = 402.1 (M + H)⁺. 20

E and F ¹H NMR (400 MHz, DMSO-d6): δ 8.37 (s, 1H), 8.20 (s, 1H), 7.81(s, 1H), 7.71-7.66 (m, 5H), 7.50-7.46 (m, 1H), 7.38-7.37 (m, 1H), 4.45(s, 3H), 3.88 (s, 2H), 2.80-2.65 (m, 4H), 1.72-1.61 (m, 4H), 1.458 (m,2H) and LC-MS m/z = 427.3 (M + H)⁺. 21

E and F ¹H NMR (400 MHz, DMSO-d6): δ 12.2 (bs, 1H), 8.34 (s, 1H), 8.21(s, 1H), 7.91-7.81 (m, 4H), 7.70-7.63 (m, 2H), 7.46-7.36 (m, 2H), 4.40(s, 3H), 3.73 (s, 2H), 3.45-3.40 (m, 4H), 1.80-1.65 (m, 4H) and LC-MSm/z = 413.3 (M + H)⁺. 22

E and F ¹H NMR (400 MHz, DMSO-d6): δ 12.2 (bs, 1H), 8.58 (s, 1H), 8.35(s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.67- 7.65(m, 2H), 7.49-7.45 (m, 1H), 7.35-7.33 (m, 1H), 4.52 (s, 3H), 3.65 (s,2H), 2.87- 2.67 (m, 4H), 2.62-2.56 (m, 4H), 2.50 (s, 3H) and LC-MS m/z =442.3 (M + H)⁺. 23

E and F ¹H NMR (400 MHz, DMSO-d6): δ 12.36 (bs, 1H), 8.51 (m, 1H), 8.37(s, 1H), 7.92- 7.80 (m, 4H), 7.68-7.64 (m, 2H), 7.48-7.44 (m, 1H),7.35-7.33 (m, 1H), 4.58 (s, 3H), 3.63 (s, 2H), 2.56-2.45 (m, 4H),1.54-1.23 (m, 6H) and LC-MS m/z = 427.3 (M + H)⁺. 24

F ¹H NMR (400 MHz, DMSO-d6): δ 8.33 (s, 1H), 8.03 (s, 1H), 7.59-7.45 (m,5H), 4.59 (s, 3H) and LC-MS m/z = 402.1 (M + H)⁺. 25

E and F ¹H NMR (400 MHz, DMSO-d6): δ 8.67 (s, 1H), 8.43 (s, 1H),7.96-7.94 (m, 3H), 7.54- 7.50 (m, 4H), 7.41-7.40 (m, 1H), 4.53 (s, 3H).4.38 (bs, 2H), 3.77-3.72 (m, 4H), 3.15 (m, 2H), 2.82 (m, 2H) and LC-MSm/z = 429.3 (M + H)⁺. 26

E and F ¹H NMR (400 MHz, DMSO-d6): δ 13.36 (s, 1H), 8.56 (s, 1H), 8.41(s, 1H), 7.95 (d, J = 8 Hz, 2H), 7.81 (m, 1H), 7.59-7.51 (m, 4H),7.44-7.42 (m, 1H), 4.59 (s, 3H), 4.40 (bs, 2H), 3.82-3.72 (m, 4H), 3.18(m, 2H), 2.82 (m, 2H) and LC-MS m/z = 429.3 (M + H)⁺. 27

E and F ¹H NMR (400 MHz, DMSO-d6): δ 13.78 (bs, 1H), 8.67 (s, 1H), 8.42(s, 1H), 8.04 (m, 1H), 7.97 (d, J = 8 Hz, 2H), 7.53-7.40 (m, 4H),7.39-7.38 (m, 1H), 4.52 (s, 3H), 4.39 (s, 2H), 3.4 (m, 2H), 2.79 (m,2H), 1.81 (m, 4H) and LC-MS m/z = 413.2 (M + H)⁺. 28

E and F ¹H NMR (400 MHz, DMSO-d6): δ 13.36 (s, 1H), 8.56 (s, 1H), 8.40(s, 1H), 7.96 (d, J = 8 Hz, 2H), 7.91-7.89 (m, 1H), 7.55-7.39 (m, 5H),4.59 (s, 3H), 4.41 (s, 2H), 3.32 (m, 2H), 2.81 (m, 2H), 1.81 (m, 4H) andLC- MS m/z = 413.3 (M + H)⁺. 29

E and F ¹H NMR (400 MHz, DMSO-d6): δ 13.21 (s, 1H), 8.66 (s, 1H), 8.42(s, 1H), 7.92 (d, J = 8 Hz, 2H), 7.55 (d, J = 8 Hz, 2H), 7.47 (m, 2H),7.37 (m, 2H), 4.52 (s, 3H), 3.56 (s, 2H), 3.40 (m, 2H), 3.14 (m, 4H),2.74 (s, 3H) and LC-MS m/z = 442.3 (M + H)⁺. 30

E and F ¹H NMR (400 MHz, DMSO-d6): δ 13.26 (s, 1H), 8.55 (s, 1H), 8.40(s, 1H), 7.92 (d, J = 8 Hz, 2H), 7.56 (d, J = 8 Hz, 2H), 7.48 (m, 2H),7.38 (m, 2H), 4.59 (s, 3H), 3.93 (m, 2H), 3.44-3.42 (m, 4H), 3.16-3.14(m, 4H), 2.77 (s, 3H) and LC-MS m/z = 442.3 (M + H)⁺. 31

E and F ¹H NMR (400 MHz, DMSO-d6): δ 8.63 (s, 1H), 8.39 (s, 1H), 7.92(d, J = 8 Hz, 2H), 7.82 (d, J = 8 Hz, 2H), 7.73 (d, J = 8 Hz, 2H), 7.45(d, J = 8 Hz, 2H), 4.52 (s, 3H), 3.61 (m, 6H), 2.74-2.61 (m, 4H) andLC-MS m/z = 429.3 (M + H)⁺. 32

F ¹H NMR (400 MHz, DMSO-d6): δ 13.8 (bs, 1H), 10.06 (s, 1H), 8.63 (d, J= 1.6 Hz, 1H), 8.38 (d, J = 1.6 Hz, 1H), 7.98-7.93 (m, 3H), 7.75 (d, J =8.4 Hz, 2H),7.61-7.58 (m, 1H), 7.42-7.40 (m, 2H), 4.52 (s, 3H), 2.05 (s,3H) and LC-MS m/z = 387.1 (M + H)⁺. 33

E and F ¹H NMR (400 MHz, DMSO-d6): δ 13.98 (bs, 1H), 8.63 (s, 1H), 8.25(s, 1H), 7.78- 7.70 (m, 4H), 4.55 (s, 3H), 4.53 (s, 2H), 3.93-3.79 (m,4H), 3.21 (m, 4H) and LC- MS m/z = 501.2 (M + H)⁺. 34

E and F ¹H NMR (400 MHz, DMSO-d6): δ 8.39 (s, 1H), 8.07 (s, 1H),7.65-7.54 (m, 4H), 4.54 (s, 3H), 3.87 (s, 2H), 2.68 (m, 4H), 1.63 (m,4H), 1.47 (m, 2H) and LC-MS m/z = 499.2 (M + H)⁺. 35

E and F ¹H NMR (400 MHz, DMSO-d6): δ 12.4 (bs, 1H), 8.4 (s, 1H), 8.04(s, 1H), 7.51-7.49 (m, 4H), 4.55 (s, 3H), 3.63 (s, 3H), 2.74-2.67 (m,6H), 2.25-2.22 (m, 4H) and LC-MS m/z = 514.2 (M + H)⁺. 36

E and F ¹H NMR (400 MHz, DMSO-d6): δ 9.8 (s, 1H), 8.11 (s, 1H), 7.90 (s,1H), 7.85 (s, 1H), 7.64-7.53 (m, 3H), 4.53 (s, 3H), 4.24 (s, 2H),3.36-3.16 (m, 1H), 1.34 (d, J = 6.4 Hz, 6H) and LC-MS m/z = 473.2 (M +H)⁺. 37

E and F ¹H NMR (400 MHz, DMSO-d6): δ 13.98 (bs, 1H), 8.95 (s, 1H), 8.63(s, 1H), 8.25 (s, 1H), 7.71-7.65 (m, 4H), 4.55 (s, 3H), 4.26 (s, 2H),2.63 (s, 3H) and LC-MS m/z = 445.1 (M + H)⁺. 38

E and F ¹H NMR (400 MHz, DMSO-d6): δ 13.46 (bs, 1H), 8.53 (s, 1H), 8.19(s, 1H), 7.82- 7.69 (m, 4H), 4.62 (s, 3H), 4.37 (s, 2H), 2.88-2.66 (m,2H), 1.79-1.68 (m, 5 H) 1.38- 1.23 (m, 2H) and LC-MS m/z = 499.2 (M +H)⁺. 39

E and F ¹H NMR (400 MHz, DMSO-d6): δ 13.48 (bs, 1H), 8.54 (s, 1H), 8.19(s, 1H), 7.81- 7.72 (m, 4H), 4.62 (s, 3H), 4.46 (s, 2H), 3.98 (m, 2H),3.78-3.72 (m, 2H), 3.15 (m, 4H) and LC-MS m/z = 501.2 (M + H)⁺. 40

E and F ¹H NMR (400 MHz, DMSO-d6): δ 13.8 (bs, 1H), 8.62 (s, 1H), 8.25(s, 1H), 7.78-7.70 (m, 4H), 4.55 (s, 3H), 4.38 (s, 2H), 2.75 (s, 6H) andLC-MS m/z = 459.2 (M + H)⁺.

PHARMACOLOGICAL ACTIVITY Measurement of DHODH Inhibitory Enzyme Activity(In Vitro Assays)

The DHODH activity assay is a coupled enzyme assay in which oxidation ofDHO and subsequent reduction of ubiquinone are stoichiometricallyequivalent to the reduction of DCIP (2,6-dichlorophenol). The reductionof DCIP is accompanied by a loss of absorbance at 610 nm.

Preparation of solutions/reagents:

Buffer Preparation: 50 mM tris HCl, 150 mM KCl, and pH 8.0, 0.8% triton.

L-Dihydroorotic acid stock solution of 20 mM in buffer.

2,6-Dichloroindophenol Sodium salt hydrate stock solution of 20 mM inbuffer.

Decylubiquinone stock solution of 20 mM in buffer.

DMSO used as vehicle.

Procedure

5 μK of Dimethyl sulfoxide or a compound of formula (I) in DMSO solutionwas added to the wells of a 96 well plate. Compounds of formula (I) weremeasured at 10 μM.

Protein along with buffer was added, so that the total volume includingthe DMSO was 87 μL. Compound and protein were incubated for half an hourat room temperature after mixing. 5 μL of 20 mM solution ofL-Dihydroorotic acid, 5 μL of 2 mM solution of Decylubiquinone and 3μLof 2 mM solution of 2, 6-Dichloroindophenol sodium salt hydrate wereadded to the above solution (total assay volume 100 μL). The mixture wasstirred for 2 min and absorbance was recorded at every 10 min at 610nanometers.

Percent inhibition is calculated as follows:

100* {(Abs₆₁₀ for reaction containing compound)−(Abs₆₁₀ for positivecontrol)

(Abs₆₁₀ for no enzyme reaction)−(Abs₆₁₀ for positive control)

Reaction containing compound has compound, buffer, enzyme and substrates

Positive control contains DMSO, buffer, enzyme and substrates

No Enzyme reaction contains DMSO, buffer and substrates

IC₅₀ Determination

A 2 mM DMSO stock solution of the selected trisubstituted benzoimidazoleand benzotriazole derivatives of formula (I) of the present invention tobe examined was prepared. Subsequent ⅓rd dilutions were made.

5 μL of each stock of compound of formula (I) was used for each 100 μLassay. Therefore, 5 μL of the 2 mM stock provided 100 μL of 100 μMsolution of compound of formula (I), when made up with buffer, proteinand substrate. See also: Ulrich et al. (2001) Eur. J. Biochem.268,1861-1868.

IC₅₀ values of the selected compounds of present invention were providedin below table, Compounds exhibiting IC₅₀ values≤0.1 μM were grouped as‘a’, compounds exhibiting IC₅₀ value in the range 0.101 μM to 1.0 μMwere grouped as ‘b’ and the compounds exhibiting IC₅₀ value>1.0 μM weregrouped as ‘c’.

TABLE DHODH inhibition activity of the selected compounds. GroupCompound No's a 1, 2, 8, 12, 19, 24. b 3, 4, 11, 13, 25, 29, 33, 34, 36,38, 39, 40. c 15, 16, 17, 20, 26, 27, 30, 31, 32, 35, 37.

Cell Based Activity Ramos Proliferation Assay (In Vitro Assays)

Cell proliferation assay is a sensitive method for quantification ofviable cells in cytotoxicity or proliferation assay. The XTT(2,3-bis[2-Methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxyanilide inner salt) system is a means ofmeasuring the activity of living cells via mitochondrial dehydrogenases.Mitochondrial dehydrogenases of viable cells cleave the tetrazolium ringof XTT, yielding orange formazon crystals which are soluble in aqueoussolutions. The XTT solution is potentiated by the addition of anelectron coupling agent, phenazine methosulphate (PMS) to the reaction.The resulting orange colour is spectrophotometrically measured at 450nm. An increase or decrease in cell numbers results in a concomitantchange in the amount of formazon formed, indicating the degree ofcytotoxicity caused by the test material [1,2].

Preparation of Solutions/Reagents

Media preparation:

Dissolve 17.7 g IMDM (Iscove's Modified Dulbecco's Medium) powder, 1.5 gsodium bicarbonate pH 7.2-7.4 in 1 L MiliQ water, add 1%Pencilin/Streptomycin and 10% FBS.

Dissolve 10.6 g Ham's F12 powder, 1.5 g sodium bicarbonate pH 7.2-7.4 in1L MiliQ water, add 1% Pencilin/Streptomycin.

DMSO used as vehicle.

1×PBS (Phosphate Buffered Saline): Dissolve 5 tablets of PBS (Sigma:Cat#P4417) in 1L MiliQ water.

Procedure (IC₅₀ Determination)

Ramos cells were re-suspended to a density of 1×10⁵ cells/ml in completeIMDM medium. 95 μL of this cell suspension was added to the 96-wellplate to seed ˜10,000 cells per well. The plates were incubated at 37°C. under a humidified atmosphere of 5% CO₂ for ˜1 hour before compoundaddition.

Test compounds (Refer to Table 1) were dissolved in 100% DMSO togenerate a 2/6/10/20 mM stock solution. A 200× concentration of therequired final concentrations was prepared in DMSO. 10 μL of eachconcentration (200×) was then diluted in 90 μL of serum-free Ham's F12medium to get an intermediate concentration of 20× in medium. The DMSOconcentration in this step is 10% (Intermediate dilution). 5 μL of eachintermediate dilution was then added in triplicates in the previouslyseeded 96-well plate. The final DMSO concentration was 0.5% in theexperimental wells. Cells treated with 0.5% DMSO served as positivecontrol. 100 μL of complete IMDM medium served as media blank for dataanalysis. 200 μL of 1×PBS was added in all corner wells of the assayplate. Plates were then incubated for 72 hours in an incubator with 5%CO₂ at 37° C.

On termination day, 100 μl of XTT solution (1 mg/ml XTT supplementedwith 25 μM PMS in Ham's F12 medium) was added to each well. Plates wereincubated for 2 hours. The amount of formazon produced was determined byreading the absorbance of the plate using VICTOR X5 multilabel platereader at wavelength of 450 nm. The IC₅₀ values were determined asconcentrations that reduced cell viability by 50% and the curve wasplotted with GraphPad Prism 6.0.

Percent Inhibition is Calculated as Follows

Percent (%) Inhibition was calculated by normalizing DMSO control valuesto 100% using the formula:

%Inhibition=100%−(Abs450_(test compound-blank))/AbS450_(positive control-blank))*100

Test compound contains cells, test compound, IMDM medium and 0.5% DMSO

Positive control contains cells, IMDM medium and 0.5% DMSO

Blank contains IMDM medium

Comp. Maximum % Inhibition IC ₅₀ No. at 30 μM (μM) 1 107 0.049 2 951.086 3 113 0.524 4 107 1.453 8 103 0.154 11 67 (at 10 μM) ND 12 1030.362 13 100 3.882 15 96 8.406 16 124 6.141 17 50 ND 19 106 0.07 20 1293.717 24 104 0.4 25 120 2.819 26 133 4.255 27 89 3.05 29 81 8.968 30 56ND 31 81 (at 10 μM) 1.349 32 74 14.58 34 111 (at 10 μM)  0.675 38 921.601 39 96 1.869 40 84 11.85

1-17. (canceled)
 18. A method of treating an autoimmune disease in a subject, comprising administering a therapeutically effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein: the dotted lines [. . . . ] in the ring represent an optional bond which may be present in any stable combination; R₁ is selected from hydrogen and alkyl; R₂ is -A-R₄. A is arylene or tetrasubstituted arylene where the substituent is halogen. R₃ is selected from hydroxy and amino; R₄ is selected from an optionally substituted aryl and an optionally substituted heteroaryl; wherein the optional substituent for the aryl and the heteroaryl selected from one or more R₅; R₅ is selected from alkyl and —(CH₂)_(n)N(R_(a))R_(b); R_(a) and R_(b) are each independently selected from hydrogen, alkyl and —C(O)alkyl; alternatively R_(a) and R_(b) can be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-6 membered heterocyclyl containing 0-2 additional heteroatoms independently selected from O and N; wherein the optional substituent for the 4-6 membered heterocyclyl is alkyl; and ‘n’ is an integer selected from 0 and
 1. 19. The method according to claim 18, wherein the autoimmune disease is selected from systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel diseases, biliary cirrhosis, uveitis and other disorders such as Crohn's diseases, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves ophthalmopathy, atopic dermatitis and asthma.
 20. The method according to claim 18, wherein the autoimmune disease is responsive to inhibition of dihydroorotate dehydrogenase.
 21. The method according to claim 18, wherein R₁ is methyl.
 22. The method according to claim 18, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 23. The method according to claim 18, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 24. The method according to claim 18, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 25. The method according to claim 18, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 26. The method according to claim 18, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 27. The method according to claim 18, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 28. The method according to claim 18, wherein the compound is

or a pharmaceutically acceptable salt thereof. 